Co-stimulatory and co-inhibitory signaling is known to be essential at the late, or contracting, stage of the response to infection, concentrating specifically on adaptive immunity. However, their roles in the early, innate-mediated immunity to acute infection are poorly understood. The long-term goal of this application is to elucidate the mechanisms by which positive and negative signaling networks regulate the early phase of the immune response to infection. This study will focus on the ligand HVEM and BTLA. Our preliminary data show that during the first few days of infection, BTLA signaling suppresses bacterial clearance, and that this effect is dependent on CD8+ T cells. We hypothesize, therefore, that HVEM delivers a negative signal through BTLA fine-tuning the early, innate immune response to reduce immunopathology and provide a robust anti-bacterial response. The specific aims of this project are 1) to determine the mechanisms by which BTLA signaling on T cells acts to limit the inflammatory innate response, and 2) to elucidate the mechanisms by which BTLA signaling on T cells regulates innate immunity against infection. This study is expected to have significant positive effects on human health as it will increase our knowledge of the anti-bacterial immune response and its associated capacity for immunopathology, and will provide clues for how to design new and better therapies to combat infection and limit pathology. Acute infection has high mortality and morbidity due to the strong activation of the systems at play in the early phase of the immune response. However, the mechanisms for regulating this early phase of the immune response are not well defined. This study will probe both the stimulatory and inhibitory regulation of the early immune response by the molecule HVEM, and will guide new treatments to enhance the clearance of infection while limiting negative effects to the host. PUBLIC HEALTH RELEVANCE: Acute infection has high mortality and morbidity due to strong activation of the systems at play in the early phase of the immune response but it is unclear whether and how the immune response is negatively regulated during the early acute phase. This study will define whether and how host immune responses against acute infection are under negative regulation;these mechanisms may be important for the balance between immunity an immune-mediated injury.